Lipid metabolism plays a key role in human health and longevity. Dysregulation of lipid metabolism has been implicated in many age-related diseases. Genetic studies in both invertebrates and vertebrates have implicated the endocrine functions of adipose tissue in regulation of animal lifespan. However, it remains poorly understood how lipid metabolism is coupled to lifespan control. Preliminary studies have suggested that lipases and lipid chaperones exert exquisite control over lipid metabolism and lifespan in C. elegans. Lipases and lipid chaperones are up-regulated in long-lived animals, and are necessary for longevity. Their functions are also pivotal for fat mobilization in wild type and long-lived mutants. Overexpression of the lipase K04A8.5 in fat storage tissue promotes lipolysis as well as longevity. These studies suggest novel mechanisms for lipid metabolism in aging. This proposal seeks to dissect the function of lipid metabolism in regulation of longevity through the following specific aims: 1) Study the mechanisms by which lipase overexpression extends lifespan. 2) Characterize the roles of lipid chaperones in lifespan regulation. 3) Identify lipid messengers that extend lifespan. We will apply genetic techniques to probe genetic interactions among lipases, lipid chaperones and known lifespan regulatory signaling, and also screen for upstream regulatory factors. Additionally, we will employ biochemical and proteomic methodologies to study lipid chaperone complexes and lipidomic approaches with the goal of identifying particular lipid species and human metabolites as key regulators of aging. The long-term goal is to explore how to promote healthy aging via modulating lipid metabolism. These studies will yield insights to mechanisms by which lipid metabolism affects the aging process, and provide novel therapeutic targets. This application describes an integrative plan that will facilitate my transition to an independent position at an academic institution. PUBLIC HEALTH RELEVANCE: Results from this study are important for public health as increased incidence of diseases with age. This study will provide insight into essential roles of lipid metabolism in regulating lifespan as well as address many fundamental issues in lipid metabolism and energy homeostasis.